Field of the Invention
The invention is generally related to increasing the bioavailability of bioactive compounds which are administered or taken orally, and more particularly, to using compounds which are generally regarded as safe (GRAS), particularly certain phenolic compounds, to prevent or decrease pre-systemic or systemic metabolism or clearance of the bioactive compounds.
Description of the Prior Art
Increasing the bioavailablity of compounds provided to a subject to treat various diseases has been a subject of intense investigation for a number of years. Furthermore, there have been a number of approaches that have employed compositions that include a drug in combination with substances that are Generally Regarded As Safe (GRAS) compounds.
U.S. Pat. No. 5,972,382 to Majeed et al. teaches compositions and methods for the improvement of gastrointestinal absorption and systemic utilization of nutrients and nutritional supplements by combining them with piperine, an alkaloid derived from black pepper. Majeed does not discuss the delivery of drugs per se, and piperine is not a GRAS compound.
U.S. Pat. No. 7,576,124 to Harris describes “first-pass” inhibiting furocoumarin compounds that are purportedly safe and effective. The furocoumarins are citrus-derived substances prepared from, e.g., grapefruit. Harris does not identify which components of pre-systemic metabolism are inhibited, but the cytochrome P450 family of enzymes is referenced. The furocoumarins are not described as GRAS.
U.S. Pat. No. 7,125,564 to Chen et al. discusses problems associated with first-pass degradation of bioactive treatment compounds, and teaches the use of water-soluble complexes with glycyrrhizin, which is the main sweet-tasting compounds from licorice root. Glycyrrhizin is described as GRAS. Chen does not indicate that glycyrrhizin can inhibit first pass metabolism; rather, Chen discusses having the compositions parenterally administered to avoid the first-pass effect.
U.S. Pat. No. 7,070,814 to Qazi et al. teaches compositions which are purportedly bioenhancing/bioavailability-facilitating. These compositions include an extract and/or at least one bioactive fraction from the Cuminum cyminum plant (i.e., the plant from which the spice cumin is derived). This extract is combined with drugs, nutrients, vitamins, nutraceuticals, herbal drugs/products, micro nutrients, and antioxidants, along with pharmaceutically acceptable additives/excipients. Similar to the Majeed patent, Qazi discusses optionally including piperine (or extract/fraction of piper nigrum or piper longum) to purportedly increase the beneficial effect of the extract. Qazi is particularly focused on the problem of pre-systemic metabolism of drugs and suggests that the compositions described in the patent may function by inhibiting or reducing the rate of biotransformation of drugs in the liver or intestines. Qazi does not identify the extract as including GRAS compounds.
U.S. Pat. No. 6,180,666 to Wacher et al. describes orally co-administering a compound of interest with a gallic acid ester such as octyl gallate, propyl gallate, lauryl gallate, and methyl gallate. Gallic acid is a trihydroxybenzoic acid, a type of organic phenolic acid found in plants such as gallnuts, sumac, witch hazel, tea leaves, and oak bark. The gallic acid ester is purportedly present in order to inhibit biotransformations of drugs that are carried out e.g. by cytochromes P450. The esters are described as GRAS compounds.
U.S. Pat. No. 6,121,234 to Benet et al., describes a method for purportedly increasing bioavailability and reducing inter- and intra-individual variability of an orally administered hydrophobic pharmaceutical compound. In Benet, the pharmaceutical compound is orally co-administered with an essential oil or essential oil component. Benet suggests that the role of the essential oil may be to inhibit drug biotransformation in the gut. Essential oils are described as GRAS compounds.
US patent application 2003/0215462 to Wacher et al. describes using UDP-glucuronosyltrasnsferase (UGT) inhibitors to increase the bioavailability orally administered drugs. Wacher suggests the formulation may be used with 2-methoxyestradiol, raloxifene, irinotecan, SN-38, estradiol, labetalol, dilevalol, zidovudine (AZT) and morphine. The UDP-inhibitors are generally natural products and include epicatechin gallate, epigallocatechin gallate, octyl gallate, propyl gallate, quercetin, tannic acid, benzoin gum, capsaicin, dihydrocapsaicin, eugenol, gallocatechin gallate, geraniol, menthol, menthyl acetate, naringenin, allspice berry oil, N-vanillylnonanamide, clovebud oil, peppermint oil, silibinin, and silymarin. Wacher does not list resveratrol and phenylephrine as exemplary drugs, nor are the GRAS substances propyl paraben, vanillin, vitamin C and curcumin identified as being useful in Wacher. The objective of the Wacher technology appears to be the identification of specific combinations of drugs and inhibitors that work well together. Wacher notes that “ . . . a compound that inhibits the glucuronidation of one substrate does not necessarily prevent the glucuronidation of all UGT substrates . . . ”.
US patent applications 2006/0040875 and 2009/0093467 to Oliver et al. describe UGT2B inhibitors that can increase the bio-availability of drugs. Specifically named inhibitors are natural products such as capillarisin, isorhamnetin, β-naphthoflavone, α-naphthoflavone, hesperetin, terpineol, (+)-limonene, β-myrcene, swertiamarin, eriodictyol, cineole, apigenin, baicalin, ursolic acid, isovitexin, lauryl alcohol, puerarin, trans-cinnamaldehyde, 3-phenylpropyl acetate, isoliquritigenin, paeoniflorin, gallic acid, genistein, glycyrrhizin, protocatechuic acid, ethyl myristate, and umbelliferone. Suggested drugs for which bioavailability can be increased include morphine, naloxone, nalorphine, oxymorphone, hydromorphone, dihydromorphine, codeine, naltrexone, naltrindole, nalbuphine and buprenorphine. The focus of Oliver is on the delivery of analgesics.
US patent application 2010/0087493 to Kaivosaari et al. teaches a method for increasing bioavailability of a pharmacologically active agent that undergoes direct N-glucuronidation by UDP-glucuronosyltransferase isoenzyme UGT2B10 by administering an UGT2B10 modulator, e.g. an inhibitor of UGT2B10 (preferably selectively for UGT2B10 over UGT1A4). The drugs for which bioavailability may be increased are described as having a nucleophilic nitrogen atom, including primary, secondary and tertiary aryl- and alkylamines, sulfonamides and aromatic or aliphatic heterocyclic compounds having one or more nitrogen atoms as heteroatoms. Nicotine is identified as an example. The inhibitors are not described in detail, and only Levomedetomidine is provided as an example.
WO/2011/026112 describes methods of increase bioavailability of a pharmaceutically active agent by using specific inhibitors of a UGT that glucuronidates the pharmaceutically active agent. However, in WO/2011/026112, the inhibitors are described as comprising an N-acyl phenylaminoalcohol residue and a uridine moiety connected by a spacer. Thus, the use of GRAS compounds does not described in WO/2011/026112.
WO 2010015636 20100211 teaches beta-carbolin-derivatives to inhibit UGTs and thereby increase bioavailability of drugs such as antibiotics. However, the use of GRAS compounds for this purpose is not discussed.
Prior to the present invention, there has been little work on strategies to increase phenylephrine oral bioavailability, and no approaches which target enzymes which target phenylyephrine metabolism and which avoid enzymes which can result in toxicity and adverse effects.